Phacomatosis pigmentokeratotica with nephroblastoma and juvenile hypertension.

Phacomatosis pigmentokeratotica is characterized by the coexistence of an organoid epidermal naevus, follow-ing Blaschko's lines, and a large speckled lentiginous naevus, typically arranged in a chequerboard pattern. This entity has been isolated from the group of epidermal naevus syndromes and is frequently associated with extracutaneous anomalies. We report here the first observation of phacomatosis pigmentokeratotica associated with nephroblastoma. In addition to this paediatric renal tumour, the coexistence of juvenile arterial hypertension suggests an associated vascular defect. The link between the extracutaneous manifestations and cutaneous twin spot phenotype is discussed.

Upper respiratory tract involvement in the course of diffuse infiltrative lymphocytosis syndrome in HIV-1-infected patients: report of 2 cases.

Diffuse infiltrative lymphocytosis syndrome (DILS) in patients with human immunodeficiency virus (HIV) infection is characterized by persistent CD8(+) lymphocytosis with visceral lymphocytic infiltration. DILS induces a large spectrum of clinical features. We describe 2 HIV-infected patients with upper respiratory tract involvement that occurred during the course of DILS.

Anogenital pseudotumoral herpes and HIV infection: a new challenge for diagnosis and treatment.

HIV-infected patients may develop rare anogenital pseudotumoral herpes potentially mimicking epidermoid carcinoma. We assessed treatment in five new cases with a median follow-up of 3.3 years. Recurrence and clinical nucleoside analog resistance were observed in all patients. All drug treatments were only temporarily curative and clinical responses varied between patients and recurrences. Foscavir seemed to be the most appropriate second-line treatment and cidofovir or thalidomide should be considered as alternative treatments.

Anti-HPV16 E2 protein T-cell responses and viral control in women with usual vulvar intraepithelial neoplasia and their healthy partners.

T-cell responses (proliferation, intracellular cytokine synthesis and IFNγ ELISPOT) against human papillomavirus 16 (HPV16) E2 peptides were tested during 18 months in a longitudinal study in eight women presenting with HPV16-related usual vulvar intraepithelial neoplasia (VIN) and their healthy male partners. In six women, anti-E2 proliferative responses and cytokine production (single IFNγ and/or dual IFNγ/IL2 and/or single IL2) by CD4+ T lymphocytes became detectable after treating and healing of the usual VIN. In the women presenting with persistent lesions despite therapy, no proliferation was observed. Anti-E2 proliferative responses were also observed with dual IFNγ/IL2 production by CD4+ T-cells in six male partners who did not exhibit any genital HPV-related diseases. Ex vivo IFNγ ELISPOT showed numerous effector T-cells producing IFNγ after stimulation by a dominant E2 peptide in all men and women. Since the E2 protein is absent from the viral particles but is required for viral DNA replication, these results suggest a recent infection with replicative HPV16 in male partners. The presence of polyfunctional anti-E2 T-cell responses in the blood of asymptomatic men unambiguously establishes HPV infection even without detectable lesions. These results, despite the small size of the studied group, provide an argument in favor of prophylactic HPV vaccination of young men in order to prevent HPV16 infection and viral transmission from men to women.

Unique functional status of natural killer cells in metastatic stage IV melanoma patients and its modulation by chemotherapy.

PURPOSE: Immunotherapy is an alternative for metastatic melanoma patients resistant to chemotherapy. Natural killer (NK) cells are powerful antileukemia effectors and their role in solid tumors is suspected. NK cell activation is regulated by a balance between activating receptors, which detect stress molecules on tumor cells, and HLA-I specific inhibitory receptors. Here, we studied the phenotype and function of NK cells in stage IV metastatic melanoma patients. EXPERIMENTAL DESIGN: Circulating NK cells from 35 healthy donors and 51 patients were studied: 24 patients before chemotherapy (prechemotherapy), 17 patients 1 month after 1 to 4 lines of chemotherapy (postchemotherapy), and 10 patients analyzed pre- and postchemotherapy. NK functionality was carried out toward 2 primary metastatic melanoma cell lines, analyzed for the expression of NK receptor ligands. RESULTS: NK cells from prechemotherapy patients exhibit an NKp46(dim)/NKG2A(dim) phenotype. In contrast, NK cells from postchemotherapy patients display high expression of NKp46 and NKG2A receptors. Purified NK cells from patients are efficiently activated in response to melanoma cells. Melanoma cells express different level of NKG2D ligands and HLA-I molecules. In agreements with their phenotype, NK cells from pre- and postchemotherapy patients present distinct functional status toward these primary melanoma cells. A dynamic label free assay was used to determine the pathways involved in the lysis of melanoma cells by IL-2-activated NK cells. NKG2D, NCR (natural cytotoxicity receptor), and DNAM-1 are involved in the NK-mediated lysis of melanoma cells. CONCLUSIONS: These results provide new arguments and clues to design NK cell-based immunotherapeutic strategies for melanoma patients.

Epidermodysplasia verruciformis in human immunodeficiency virus-infected patients: a marker of human papillomavirus-related disorders not affected by antiretroviral therapy.

BACKGROUND: Skin eruptions resembling epidermodysplasia verruciformis (EV) are rarely observed in immunocompromised patients. We focused on the epidemiologic, clinical, virologic, and immunologic features of EV in human immunodeficiency virus (HIV)-positive patients. OBSERVATIONS: We studied 11 HIV-positive patients (6 men and 5 women) with clinical and histological features of EV observed at our department. The median age at HIV diagnosis was 27 years. At the onset of eruption, the median age was 40 years and the median CD4 T-cell count was 170/µL. Clinical presentation included flat warts (n = 11), pityriasis versicolor-like macules (n = 5), and lichenoid papules (n = 3) on sun-exposed skin. Detection and typing of cutaneous human papillomavirus (HPV) were carried out in 8 cases and always revealed ß-HPV infection, including oncogenic HPV-5 or 8 (n = 6). Mucosal HPV-related diseases were present in 7 cases. Histories of skin cancer and lymphoproliferative disorder were recorded in 3 and 4 patients, respectively, including 2 fatal cases. Skin eruption was never improved by highly active antiretroviral therapy (HAART). In 2 cases, EV was associated with an immune reconstitution syndrome. The present series is the largest with a complete characterization. A review of similar cases was carried out. CONCLUSION: Despite effective HAART, HIV-infected patients with EV require a prolonged and careful follow-up to detect mucosal HPV-related diseases, lymphoproliferative disorders, and skin cancers.

Progressive upregulation of PD-1 in primary and metastatic melanomas associated with blunted TCR signaling in infiltrating T lymphocytes.

Programmed death-1 (PD-1) is involved in T-cell tolerance to self-antigens. For some cancers, it has been suggested that the expression of a ligand of PD-1, namely PD-L1, could contribute to tumor escape from immune destruction. Nevertheless, the relationship between PD-1 expression on tumor-infiltrating T lymphocytes (TILs), disease stage, and TIL responsiveness is still poorly documented. In this study, we show that freshly isolated CD4(+) and CD8(+) TILs express substantial levels of PD-1 in primary melanomas. The expression of PD-1 was further increased at later stages in distant cutaneous metastases, especially on CD8(+) TILs. The expression of PD-1 ligands was frequent only in metastases, on both tumor cells and tumor-derived myeloid cells. TILs isolated from these cutaneous tumors are poorly reactive ex vivo, with blunted calcium response and IFN-γ production after TCR stimulation. Surprisingly, in distinct parts of a primary melanoma, either invasive or regressing, we show that TILs similarly express PD-1 and remain dysfunctional. The expressions of PD-1 and PD-L1 in metastatic melanoma lesions could be considered as witnesses of an unsuccessful anti-tumoral immune response, but the direct involvement of PD-1 in the severity of the disease, and the importance of TILs in tumor regression, remain to be established.